Dimethyl fumarate

Dimethyl fumarate
Names
IUPAC name
Dimethyl (E)-butenedioate
Other names
trans-1,2-Ethylenedicarboxylic acid dimethyl ester
(E)-2-Butenedioic acid dimethyl ester
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
DrugBank
ECHA InfoCard 100.009.863
EC Number 210-849-0
UNII
Properties
C6H8O4
Molar mass 144.127 g/mol
Appearance White crystalline solid
Density 1.37 g/cm3, solid
Melting point 102 to 105 °C (216 to 221 °F; 375 to 378 K)[1]
Boiling point 192 to 193 °C (378 to 379 °F; 465 to 466 K)[1]
Pharmacology
N07XX09 (WHO)
Hazards
Harmful (Xn)
R-phrases (outdated) R21 R38 R41 R43
S-phrases (outdated) S26 S36 S37 S39
Related compounds
Related diesters
 Diethyl fumarate, dimethyl maleate, dimethyl malonate, dimethyl adipate
Related compounds
 Fumaric acid
Methyl acrylate
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Dimethyl fumarate (DMF) is the methyl ester of fumaric acid. DMF was initially recognized as a very effective hypoxic cell radiosensitizer.[2] Later, DMF combined with three other fumaric acid esters (FAE) was licensed in Germany as oral therapy for psoriasis (trade name Fumaderm).[3] Other diseases, such as necrobiosis lipoidica, granuloma annulare, and sarcoidosis were also found to respond to treatment with DMF in case reports or small patient series.[4] Phase III clinical trials found that DMF (BG-12) successfully reduced relapse rate and increased time to progression of disability in multiple sclerosis (trade name Tecfidera).[5][6] DMF is thought to have immunomodulatory properties without significant immunosuppression.[7]

In a non-medical use, DMF was applied as a biocide in furniture or shoes to prevent growths of mold during storage or transport in a humid climate. However, due to incidences of allergic reactions after skin contact the European Union banned DMF in consumer products since 1998, and since January 2009 the import of products containing DMF was also banned.[8]

Medical use

Dimethyl fumarate was shown to have a significant effect on relapse rate and time to progression in phase III clinical trials of multiple sclerosis.[5][6]

Dimethyl fumarate was recommended for approval in the European Union as a peroral treatment for MS by EMA on March 21, 2013.[9]

Side effects

One serious side effect that has been described is progressive multifocal leukoencephalopathy.[10]

Reactions

Dimethyl fumarate is an ester and an α,β-unsaturated electrophilic compound which can quickly undergo Michael additions with nucleophiles. Dimethyl fumarate is also an effective diene acceptor in the thermal Diels-Alder reaction, where the reactivity of its vinylenic bond is enhanced by the two electron-withdrawing ester groups. Due to the geometry of the starting ester, the Diels-Alder product will have a trans configuration. With this reaction, compounds with bicyclo skeletons can be synthesized, e.g. a diester with a norbornene (bicyclo[2.2.1]heptene) skeleton from dimethyl fumarate and cyclopentadiene.

Mechanism of action

The precise mechanism of action of dimethyl fumarate is unknown. The compound (and its metabolite, monomethyl fumarate) activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway and has been identified as a nicotinic acid receptor agonist in vitro.[11] Dimethyl fumarate is a lipophilic, highly mobile molecule in human tissue. As a α,β-unsaturated electrophilic compound, dimethyl fumarate is rapidly attacked by the detoxifying agent glutathione (GSH) in a Michael addition reaction.[12][13][14] Dimethyl fumarate is highly reactive: when administered orally, it does not survive long enough to be absorbed into blood without being attacked by GSH. However, part of it is hydrolyzed by esterases to produce monomethylfumarate, which is more resistant.[15]

History

The American company Biogen Idec developed DMF as a capsule containing microtablets for the treatment of multiple sclerosis, under the code name BG-12; it was approved, under the trade name Tecfidera, for the treatment of adults with relapsing forms of MS on March 27, 2013.[16][17]

Consumer products

Dimethyl fumarate has been found to be an allergic sensitizer at very low concentrations, producing eczema that is difficult to treat. Concentrations as low as 1 ppm may produce allergic reactions.[18] There are only a handful of equally potent sensitizers.[19]

The sensitizing risk was brought to public attention by the "poison chair" incident, where Chinese manufacturer Linkwise produced two-seater sofas with dimethyl fumarate sachets inside to inhibit mold while they were in storage or transport.[20][21] In Finland where the chairs were sold from 2006–2007, sixty users were given serious rashes.[19] The cause was identified as dimethyl fumarate-induced allergic reaction by Tapio Rantanen from Finland, and his original article became the cover story in the July issue of the British Journal of Dermatology.[18] In the United Kingdom, sofas sold by Argos, Land of Leather and Walmsley Furnishing containing the chemical caused over a hundred injuries.[19][21] Argos withdrew the sofas from stores and contacted buyers to collect those that had been sold — with Land of Leather withdrawing the sofas without notifying buyers and Walmsley saying they had removed the sachets from sofas they sold after the danger came to light.[21] Complaints have been made that dates on the sofas were altered and sofas containing the sachets sold.[21] Land of Leather and Walmsley are facing a ₤10 million class action suit over their reaction to the incident, joining the manufacturer in denying the sofas are connected to their customers injuries.[21][22][23] The danger came to public attention when the BBC Watchdog program alerted consumers to the sofas.[21][22][24]

In the European Union the use of dimethyl fumarate for consumer products has been forbidden since 1998, and since January 2009 the import of products containing dimethyl fumarate is also forbidden.[8]

The EU Commission Decision 2009/251 of 17 March 2009 requiring Member States to ensure that products containing the biocide dimethyl fumarate are not placed or made available on the market has definitely forbidden any marketing of products containing dimethyl fumarate into the European Union.[25] The ban on dimethyl fumarate as laid down in Decision 2009/251 establishes a maximum concentration of dimethyl fumarate in products of 0.1 ppm. Products containing more than 0.1 ppm dimethyl fumarate shall be withdrawn from the market and recalled by consumers as of 1 May 2009.

References

  1. 1 2 Acros MSDS
  2. ↑ Held, Kathryn D.; Epp, Edward R.; Clark, Edward P.; Biaglow, John E. (1988). "Effect of Dimethyl Fumarate on the Radiation Sensitivity of Mammalian Cells in Vitro". Radiation Research. 115 (3): 495–502. JSTOR 3577299. PMID 3174933. doi:10.2307/3577299.
  3. ↑ Mrowietz, Ulrich; Altmeyer, Peter; Bieber, Thomas; et al. (2007). "Treatment of psoriasis with fumaric acid esters (Fumaderm®)". JDDG. 5 (8): 716–7. PMID 17659047. doi:10.1111/j.1610-0387.2007.06346.x.
  4. ↑ Meissner, Markus; Valesky, Eva Maria; Kippenberger, Stefan; Kaufmann, Roland (2012). "Dimethyl fumarate - only an anti-psoriatic medication?". JDDG. 10 (11): 793–801. PMID 22897153. doi:10.1111/j.1610-0387.2012.07996.x.
  5. 1 2 Gold, Ralf; Kappos, Ludwig; Arnold, Douglas L.; et al. (2012). "Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis". New England Journal of Medicine. 367 (12): 1098–107. PMID 22992073. doi:10.1056/NEJMoa1114287.
  6. 1 2 Fox, Robert J.; Miller, David H.; Phillips, J. Theodore; et al. (2012). "Placebo-Controlled Phase 3 Study of Oral BG-12 or Glatiramer in Multiple Sclerosis". New England Journal of Medicine. 367 (12): 1087–97. PMID 22992072. doi:10.1056/NEJMoa1206328.
  7. ↑ McEntee, Joanne. "Fumaderm®: what is the evidence for its efficacy and safety". North West Medicines Information Centre. Archived from the original on 17 November 2012. Retrieved 29 November 2012.
  8. 1 2 "Consumers: EU to ban dimethylfumarate (DMF) in consumer products, such as sofas and shoes" (Press release). European Commission. Retrieved 29 November 2012.
  9. ↑ European Public Assessment Report: Tecfidera (dimethyl fumarate), European Medicines Agency, 26 Feb 2014
  10. ↑ "FDA Drug Safety Communication: FDA warns about case of rare brain infection PML with MS drug Tecfidera (dimethyl fumarate)". fda.gov. 2014-11-25. Retrieved 2 December 2014.
  11. ↑ "Highlights of prescribing information" (PDF). Biogen Idec. March 2013. Retrieved 8 October 2014.
  12. ↑ Boyland, E; Chasseaud, LF (1967). "Enzyme-catalysed conjugations of glutathione with unsaturated compounds". The Biochemical Journal. 104 (1): 95–102. PMC 1270549 Freely accessible. PMID 6035529. doi:10.1042/bj1040095.
  13. ↑ Kubal, Gina; Meyer, David J.; Norman, Richard E.; Sadler, Peter J. (1995). "Investigations of Glutathione Conjugation in Vitro by 1H NMR Spectroscopy. Uncatalyzed and Glutathione Transferase-Catalyzed Reactions". Chemical Research in Toxicology. 8 (5): 780–91. PMID 7548762. doi:10.1021/tx00047a019.
  14. ↑ Schmidt, Thomas J.; Ak, Muharrem; Mrowietz, Ulrich (2007). "Reactivity of dimethyl fumarate and methylhydrogen fumarate towards glutathione and N-acetyl-l-cysteine—Preparation of S-substituted thiosuccinic acid esters". Bioorganic & Medicinal Chemistry. 15 (1): 333–42. PMID 17049250. doi:10.1016/j.bmc.2006.09.053.
  15. ↑ Schmidt, Thomas J.; Aka, Muharrem; Mrowietz, Ulrich (2007). "Reactivity of dimethyl fumarate and methylhydrogen fumarate towards glutathione and N-acetyl-l-cysteine—Preparation of S-substituted thiosuccinic acid esters". Bioorganic & Medicinal Chemistry. 15 (1): 333–342. PMID 17049250. doi:10.1016/j.bmc.2006.09.053.
  16. ↑ "Biogen Idec’s TECFIDERA™ (Dimethyl Fumarate) Approved in US as a First-Line Oral Treatment for Multiple Sclerosis". Biogen Idec Press Release. Mar 27, 2013.
  17. ↑ "FDA approves new multiple sclerosis treatment: Tecfidera". FDA. Mar 27, 2013. Retrieved 2013-04-05.
  18. 1 2 Rantanen, T. (2008). "The cause of the Chinese sofa/chair dermatitis epidemic is likely to be contact allergy to dimethylfumarate, a novel potent contact sensitizer". British Journal of Dermatology. 159 (1): 218–21. PMID 18503603. doi:10.1111/j.1365-2133.2008.08622.x.
  19. 1 2 3 "Myrkkytuoli-ihottumien syy selvisi". YLE Uutiset (in Finnish). YLE. 2008-04-24. Retrieved 2008-06-10.
  20. ↑ "Clifton woman's toxic sofa claim". The Nottingham Post. Local World. 2 Apr 2009.
  21. 1 2 3 4 5 6 Bracchi, Paul (21 June 2008). "This baby was burned red raw by a sofa giving off toxic fumes. As our investigation reveals, there are hundreds of other victims". Daily Mail. London: Associated Newspapers Ltd.
  22. 1 2 BBC - Consumer - TV and radio - itchy sofas Archived February 22, 2008, at the Wayback Machine.
  23. ↑ BBC: Judge rejects 'toxic sofa' claims in burns injury cases, 18 March 2010
  24. ↑ "BBC: 3 reports on dimethyl fumarate in furniture". April 2010.
  25. ↑ "2009/251/EC: Commission Decision of 17 March 2009".
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